Nakagami Hironori, Tomita Naruya, Kaneda Yasufumi, Ogihara Toshio, Morishita Ryuichi
Division of Clinical Gene Therapy, Osaka University Graduate School of MedicIine, Suita, Japan.
Curr Pharm Biotechnol. 2006 Apr;7(2):95-100. doi: 10.2174/138920106776597702.
Oxidative stress to cardiovascular cells induced by an interaction of multiple cytokines and adhesion molecules has been postulated to be responsible for cardiovascular disease. Since nuclear factor-kappaB (NFkappaB) also plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes, we utilized oligodeoxynucleotides (ODNs) as "decoy" cis-elements that block the binding of nuclear factors to promoter regions of targeted genes, resulting in the inhibition of gene transactivation. Indeed, transfection of NFkappaB decoy ODNs into coronary artery effectively prevented transactivation of essential cytokine and adhesion molecule protein expression, and thereby protected the myocardium from infarction. Transfection of NFkappaB decoy ODNs into balloon-injured carotid artery or porcine coronary artery markedly reduced neointimal formation. Thus, a clinical trial using NFkappaB decoy ODNs to treat restenosis was started in 2002. Recently, the therapeutic target utilizing NFkappaB decoy has been expanded to glomerulonephritis, rheumatoid arthritis, atopic dermatitis and osteoporosis. Moreover, the clinical trials to treat RA patients were initiated in 2003 and a Phase I/IIa human clinical trial using NFkappaB decoy ODNs to treat atopic dermatitis was initiated in December 2001. Topical application of NFkappaB decoy ODNs exhibited marked therapeutic effects on the facial skin condition of patients with atopic dermatitis. The covalently modified ODNs were developed by enzymatically ligating two identical molecules, thereby preventing their degradation by exonucleases. Indeed, the modified decoy ODNs possess increased nuclease resistance and are transported more efficiently into cells. Although there are still unresolved issues, decoy ODN drugs should become a reality.
多种细胞因子和黏附分子相互作用所诱导的心血管细胞氧化应激被认为是心血管疾病的病因。由于核因子-κB（NFκB）在细胞因子和黏附分子基因的协同反式激活中也起关键作用，我们利用寡脱氧核苷酸（ODN）作为“诱饵”顺式元件，阻断核因子与靶基因启动子区域的结合，从而抑制基因的反式激活。事实上，将NFκB诱饵ODN转染到冠状动脉中可有效防止必需细胞因子和黏附分子蛋白表达的反式激活，从而保护心肌免受梗死。将NFκB诱饵ODN转染到球囊损伤的颈动脉或猪冠状动脉中可显著减少新生内膜形成。因此，2002年启动了一项使用NFκB诱饵ODN治疗再狭窄的临床试验。最近，利用NFκB诱饵的治疗靶点已扩展到肾小球肾炎、类风湿性关节炎、特应性皮炎和骨质疏松症。此外，2003年启动了治疗类风湿性关节炎患者的临床试验，2001年12月启动了一项使用NFκB诱饵ODN治疗特应性皮炎的I/IIa期人体临床试验。局部应用NFκB诱饵ODN对特应性皮炎患者的面部皮肤状况显示出显著的治疗效果。通过酶促连接两个相同分子开发了共价修饰的ODN，从而防止其被核酸外切酶降解。事实上，修饰后的诱饵ODN具有更高的核酸酶抗性，并且能更有效地转运到细胞中。尽管仍有未解决的问题，但诱饵ODN药物应该会成为现实。
